Sequence Dependent Barriers to Nucleosome Unwrapping

Abstract

The nucleosome core particle (NCP) is the basic packaging unit of DNA. Recently reported structures of the NCP suggest that the histone octamer undergoes conformational changes during the process of DNA translocation around the histone octamer [1]. We perform long-time MD simulations of the nucleosome core particle in aqueous medium at varying salt concentrations to explore the unwrapping process [2]. Initial results show the formation of a loop/bulge of nucleosomal DNA after 2 microsecond simulation that continues to grow throughout our 5 microseconds simulation. Indeed, the loop structure agrees well with recently reported cryoEM studies of the distorted nucleosome core particle (NCP) [1]. Next, we explore with additional longer trajectories the process of nucleosome unwrapping at varying salt concentrations, comparing two nucleosomal DNA sequences, the alpha-satellite palindromic (ASP) nucleosomal DNA sequence and the Widom-601 sequence. We also probe the free energy profiles of nucleosome unwrapping that are associating with the ASP and Widom-601 sequence using Umbrella Sampling. Our results provide insight into the critical sequence-dependent barriers to nucleosome unwrapping.